Schweinfurthin analogues

ABSTRACT

Methods and intermediates for preparing enantiomerically enriched Schweinfurthin analogs which are useful for the treatment of cancer, as well as novel Schweinfurthin analogs having anti-cancer activity, compositions comprising such analogs and therapeutic methods comprising administering such analogs.

RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 11/093,270 filed onMar. 29, 2005, now U.S. Pat. No. 7,358,377 which claims the benefit ofUnited States Provisional Patent Application Number 60/557,243, filed 29Mar. 2004; which applications are incorporated herein by reference andmade a part hereof.

GOVERNMENT FUNDING

The invention described herein was made with government support underGrant Numbers DAMD17-01-1-0276 and DAMD17-02-1-0423 awarded by the USDepartment of Defense, Breast Cancer Research Program. The United StatesGovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

The family of natural products known as the schweinfurthins includesfour compounds (FIG. 1, 1-4) isolated from the African plant Macarangaschweinfurthii Pax (see Beutler, J. A. et al., J. Nat. Prod. 1998, 61,1509-1512; and Beutler, J. A., et al., Nat. Prod. Lett. 2000, 14,349-404). Schweinfurthins A (1), B (2), and D (4) display significantactivity in the NCI's 60-cell line anticancer assay with mean GI₅₀'s <1μM. Their biological activity has attracted interest because some CNS,renal, and breast cancer cell lines are among the types most sensitiveto these compounds. Inspection of the spectrum of activity shows nocorrelation with any currently used agents and suggests that thesecompounds may be acting at a previously unrecognized target or through anovel mechanism.

Repeated attempts to isolate larger samples of the schweinfurthins fromnatural sources have met with limited success; the absolutestereochemistry of these compounds has yet to be determined.

A cascade cyclization approach to the synthesis of racemicSchweinfurthin B was reported by E. Treadwell, et al., Organic Letters,2002, 4, 3639-3642. The reported synthetic method, however, could not beelaborated to provide enantiomerically enriched mixtures ofSchweinfurthin B.

Accordingly, there exists a need for synthetic methods that are usefulfor preparing enantiomerically enriched Schweinfurthin compounds. Inaddition to providing commercially useful quantities, such methods wouldallow sufficient quantities of the Schweinfurthin compounds to beprepared such that the absolute stereochemistry of the biologicallyactive natural products can be determined. Additionally, generalsynthetic methods for preparing the Schweinfurthin ring structure wouldallow the preparation of structurally related compounds that might alsohave useful biological activity.

SUMMARY OF THE INVENTION

Applicant has discovered a process for preparing enantiomericallyenriched Schweinfurthin B and D analogs. In one embodiment, theinvention provides intermediate compounds useful for preparingSchweinfurthin analogs.

The invention also provides a compound of formula (XX):

wherein:

R₇ and R₈ are each independently H or (C₁-C₆) alkyl;

R₉ is H, (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl,(C₂-C₁₅)alkanoyloxy, aryl or heteroaryl, which aryl or heteroaryl isoptionally substituted with one or more halo, hydroxy, cyano, CF₃, OCF₃,NR^(a)R^(b), (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl,(C₁-C₁₅)alkoxy(C₁-C₁₅)alkoxy, —P(═O)(OH)₂, and (C₂-C₁₅)alkanoyloxy;

R₁₀ is H or (C₁-C₆) alkyl; and

R^(a) and R^(b) are each independently H or (C₁-C₆)alkyl

wherein any (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or(C₂-C₁₅)alkanoyloxy of R₇, R₈, and R₉ is optionally substituted with oneor more halo, hydroxy, cyano, or oxo (═O).

or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of formula (XX), or a pharmaceutically acceptable salt thereof,in combination with a pharmaceutically acceptable diluent or carrier.

Additionally, the invention provides a therapeutic method for treatingcancer comprising administering to a mammal in need of such therapy, aneffective amount of a compound of formula (XX), or a pharmaceuticallyacceptable salt thereof.

The invention provides a compound of formula (XX) for use in medicaltherapy (e.g. for use in treating cancer), as well as the use of acompound of formula (XX) for the manufacture of a medicament useful forthe treatment of cancer in a mammal, such as a human.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing compounds of formula (XX) as well as otherSchweinfurthin analogs.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the structure of Schweinfurthin analogs A-D.

FIGS. 2-3 illustrates synthetic methods and intermediates useful forpreparing Schweinfurthin analogs.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: alkyl,alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups;but reference to an individual radical such as “propyl” embraces onlythe straight chain radical, a branched chain isomer such as “isopropyl”being specifically referred to. Alkenyl denotes a hydrocarbon chain withone or more (1, 2, 3, or 4) double bonds. Likewise, alkynyl denotes ahydrocarbon chain with one or more (1, 2, 3, or 4) triple bonds. Aryldenotes a phenyl radical or an ortho-fused bicyclic carbocyclic radicalhaving about nine to ten ring atoms in which at least one ring isaromatic; and heteroaryl encompasses a monocyclic aromatic ringcontaining five or six ring atoms consisting of carbon and one to fourheteroatoms each selected from the group consisting of non-peroxideoxygen, sulfur, and N(X) wherein X is absent or is H, O, (C₁-C₄)alkyl,phenyl or benzyl, as well as a radical of an ortho-fused bicyclicheterocycle of about eight to ten ring atoms derived therefrom,particularly a benz-derivative or one derived by fusing a propylene,trimethylene, or tetramethylene diradical thereto.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

The term “enantiomerically enriched” (“ee”) as used herein refers tomixtures that have one enantiomer present to a greater extent thananother. In one embodiment of the invention, the term “enantiomericallyenriched” refers to a mixture having at least about 2% ee; in anotherembodiment of the invention, the term “enantiomerically enriched” refersto a mixture having at least about 5% ee; in another embodiment of theinvention, the term “enantiomerically enriched” refers to a mixturehaving at least about 20%; in another embodiment of the invention, theterm “enantiomerically enriched” refers to a mixture having at leastabout 50%; in another embodiment of the invention, the term“enantiomerically enriched” refers to a mixture having at least about80%; in another embodiment of the invention, the term “enantiomericallyenriched” refers to a mixture having at least about 90%; in anotherembodiment of the invention, the term “enantiomerically enriched” refersto a mixture having at least about 95%; in another embodiment of theinvention, the term “enantiomerically enriched” refers to a mixturehaving at least about 98%; in another embodiment of the invention, theterm “enantiomerically enriched” refers to a mixture having at leastabout 99%.

The term “enantiomerically enriched” includes enantiomerically puremixtures which are mixtures that are substantially free of the speciesof the opposite optical activity or one enantiomer is present in verylow quantities, for example, 0.01%, 0.001% or 0.0001%.

The term “protecting group” or “blocking group” refers to any groupwhich, when bound to a hydroxy prevents undesired reactions fromoccurring at this group and which can be removed by conventionalchemical or enzymatic steps to reestablish the hydroxyl group. Theparticular removable blocking group employed is not critical andpreferred removable hydroxyl blocking groups include conventionalsubstituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl,benzylidine, phenacyl, methyl methoxy, silyl ethers (e.g.,t-butyl-diphenylsilyl or t-butylsilyl (“TBS”)) and any other group thatcan be introduced chemically onto a hydroxyl functionality and laterselectively removed either by chemical or enzymatic methods in mildconditions compatible with the nature of the product. Suitable hydroxylprotecting groups are known to those skilled in the art and disclosed inmore detail in T. W. Greene, Protecting Groups In Organic Synthesis;Wiley: New York, 1981, and the references cited therein.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

Specifically, (C₁-C₁₅)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, t-butyl, pentyl, 3-pentyl, hexyl, heptyl,octyl, nonyl, decyl, do-decyl, hexadecyl, octadecyl, icosyl;(C₁-C₁₅)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy,iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C₂-C₁₅)alkenylcan be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C₂-C₁₅)alkynyl can beethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, or 5-hexynyl; (C₁-C₁₅)alkanoyl can be acetyl,propanoyl or butanoyl; (C₁-C₁₅)alkoxycarbonyl can be methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, or hexyloxycarbonyl; (C₂-C₁₅)alkanoyloxy can beacetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, orhexanoyloxy; aryl can be phenyl, indenyl, or naphthyl.

In one specific embodiment of the invention R₇ is H.

In one specific embodiment of the invention R₇ is (C₁-C₆) alkyl.

In one specific embodiment of the invention R₇ is methyl.

In one specific embodiment of the invention % is H.

In one specific embodiment of the invention R₈ is (C₁-C₆) alkyl.

In one specific embodiment of the invention R₈ is methyl.

In one specific embodiment of the invention R₉ is H.

In one specific embodiment of the invention R₉ is (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, (C₂-C₁₅)alkanoyloxy.

In one specific embodiment of the invention R₉ is (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, or (C₂-C₁₅)alkynyl.

In one specific embodiment of the invention R₉ is aryl optionallysubstituted with one or more halo, hydroxy, cyano, CF₃, OCF₃,NR^(a)R^(b), (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, and(C₂-C₁₅)alkanoyloxy.

In one specific embodiment of the invention R₉ is aryl optionallysubstituted with one or more halo, hydroxy, cyano, CF₃, OCF₃,NR^(a)R^(b), (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy,(C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, and (C₂-C₁₅)alkanoyloxy.

In one specific embodiment of the invention R₉ is aryl optionallysubstituted with one or more halo, hydroxy, cyano, CF₃, OCF₃,NR^(a)R^(b), (C₂-C₁₅)alkenyl, (C₁-C₁₅)alkoxy.

In one specific embodiment of the invention aryl is phenyl or naphthyl.

In one specific embodiment of the invention R₉ is of the formula

wherein:

R^(c) and R^(d) are each independently H, halo, hydroxy, (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, methoxymethoxy, and(C₂-C₁₅)alkanoyloxy; and

R^(d) is H, (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, and(C₂-C₁₅)alkanoyloxy;

wherein any (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or(C₂-C₁₅)alkanoyloxy of R^(c), R^(e), and R^(d) is optionally substitutedwith one or more halo, hydroxy, cyano, or oxo (═O).

In one specific embodiment of the invention R₉ is of the formula

wherein:

R^(e) and R^(e) are each independently H, halo, hydroxy, (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, methoxymethoxy, and(C₂-C₁₅)alkanoyloxy; and

R^(d) is H, (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, and(C₂-C₁₅)alkanoyloxy;

R^(g) is H, cyano, fluoro, or —P(═O)(OH)₂; and

R^(h) is H, cyano, fluoro, or —P(═O)(OH)₂;

wherein any (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or(C₂-C₁₅)alkanoyloxy of R^(c), R^(e), and R^(d) is optionally substitutedwith one or more halo, hydroxy, cyano, or oxo (═O).

In one specific embodiment of the invention R^(c) and R^(e) are eachindependently H, fluoro, chloro, bromo, hydroxy, or methoxy.

In one specific embodiment of the invention at least one of R^(c) andR^(e) is hydroxy.

In one specific embodiment of the invention R^(d) is (C₂-C₁₅)alkenyloptionally substituted with one or more halo, hydroxy, or oxo (═O).

In one specific embodiment of the invention R^(d) is hydrogen,trans-3,7-dimethyl-2,6-octadien-1-yl, ortrans-3,7-dimethyl-8-hydroxy-2,6-octadien-1-yl.

In one specific embodiment of the invention R₉ is isoxazolyl,imidazolyl, pyridyl, indolyl, or benzo[b]furanyl.

In one specific embodiment of the invention the compound of theinvention is isolated and purified.

In one specific embodiment the invention provides a diol of formula (II)

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₃, R₄,and R₅ are each independently a suitable hydroxy protecting group.

In one specific embodiment the invention provides an epoxide of formula(III)

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₃, R₄,and R₅ are each independently a suitable hydroxy protecting group.

In one specific embodiment the invention provides a compound of formula(IV)

wherein R₁ and R₂ are each independently H or (C₁-C₆) alkyl; and R₃ andR₅ are each independently a hydroxy protecting group.

In one specific embodiment the invention provides an alcohol of formula(V)

wherein R₁ and R₂ are each independently H or (C₁-C₆) alkyl; and R₅ is ahydroxy protecting group.

In one specific embodiment the invention provides an aldehyde of formula(VI)

wherein R₁ and R₂ are each independently H or (C₁-C₆) alkyl; and R₅ is ahydroxy protecting group.

In one specific embodiment the invention provides a stilbene of formula(VII)

wherein R₁ and R₂ are each independently H or (C₁-C₆) alkyl;

R₅ is a hydroxy protecting group; and

R₆ is aryl or heteroaryl optionally substituted with one or more halo,hydroxy, cyano, CF₃, OCF₃, NR^(a)R^(b), (C₁-C₁₅) alkyl, (C₂-C₁₅)alkenyl,(C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, and (C₂-C₁₅)alkanoyloxy; wherein any(C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy,(C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy of R₆is optionally substituted with one or more halo, hydroxy, cyano, or oxo(═O);

In one specific embodiment the invention provides a compound of formula(VIII)

wherein R₁ and R₂ are each independently H or (C₁-C₆) alkyl; and R₆ isaryl or heteroaryl optionally substituted with one or more halo,hydroxy, cyano, CF₃, OCF₃, NR^(a)R^(b), (C₁-C₁₅) alkyl, (C₂-C₁₅)alkenyl,(C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, and (C₂-C₁₅)alkanoyloxy; wherein any(C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy,(C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy of R₆is optionally substituted with one or more halo, hydroxy, cyano, or oxo(═O).

In one specific embodiment the invention provides a diol of formula (IX)

wherein R₁ and R₂ are each independently H or (C₁-C₆) alkyl; and R₆ isaryl or heteroaryl optionally substituted with one or more halo,hydroxy, cyano, CF₃, OCF₃, NR^(a)R^(b), (C₁-C₁₅) alkyl, (C₂-C₁₅)alkenyl,(C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, and (C₂-C₁₅)alkanoyloxy; wherein any(C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy,(C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy of R₆is optionally substituted with one or more halo, hydroxy, cyano, or oxo(═O).

In one specific embodiment the invention provides a compound which isenantiomerically enriched and has an enantiomeric excess of at leastabout 90%.

In one specific embodiment the invention provides a compound which isenantiomerically enriched and has an enantiomeric excess of at leastabout 95%.

In one specific embodiment the invention provides a compound which isenantiomerically enriched and has an enantiomeric excess of at leastabout 98%.

In one specific embodiment the invention provides a compound which isenantiomerically enriched and has an enantiomeric excess of at leastabout 99%.

In one specific embodiment the invention provides a compound which isenantiomerically pure.

In one specific embodiment the invention provides a compound of formula(XX) which is the SSS enantiomer.

In one specific embodiment the invention provides a compound of formula(XX) which is the RRR enantiomer.

In one specific embodiment the invention provides a pharmaceuticalcomposition comprising a compound of formula (XX), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

In one specific embodiment the invention provides A method for treatingcancer comprising administering a therapeutically effective amount of acompound of the invention to a mammal.

In one specific embodiment the invention provides a compound of theinvention for use in medical therapy.

In one specific embodiment the invention provides the use of a compoundas described in any one of claims 1-22 to prepare a medicament usefulfor treating cancer (e.g. breast cancer or a cancer of the CNS or renalsystem).

In one specific embodiment the invention provides method of preparing acompound of formula (IIa):

comprising oxidizing a diene of formula (Ia):

to provide the diol of formula (IIa).

In one specific embodiment the invention provides a method for preparingan epoxide of formula (IIIa)

comprising treating a diol of formula (IIa):

with a suitable base and mesyl chloride to provide the epoxide offormula (IIIa).

In one specific embodiment the invention provides a method of preparinga compound of formula (IVa)

comprising treating epoxide of formula (IIIa):

with tetrabutylammonium fluoride and trifluoroacetic acid to provide acompound of formula (IVa).

In one specific embodiment the invention provides a method of preparingan alcohol of formula (Va)

comprising treating a compound of formula (IVa)

with potassium carbonate and methanol to provide the compound of formula(Va).

In one specific embodiment the invention provides a method of preparingan aldehyde of formula (VIa)

comprising oxidizing the alcohol of formula (Va)

to provide the aldehyde of formula (VIa).

In one specific embodiment the invention provides a method of preparinga stilbene of formula (VIIa):

comprising reacting an aldehyde of formula (VIa):

with a phosphonate of the following formula:

to provide the stilbene of formula (VIIa)

In one specific embodiment the invention provides a method for preparinga compound of formula (VIIIa):

comprising deprotecting a corresponding compound of formula (VIIa):

by treatment with a suitable acid to provide the compound of formula(VIIIa).

In one specific embodiment the invention provides a method for preparinga diol compound of formula (IXa):

comprising converting a corresponding compound of formula (VIIIa)

to the diol.

In one specific embodiment the invention provides a compound of formula(IIa):

In one specific embodiment the invention provides an enantiomericallyenriched compound of formula (IIIa):

In one specific embodiment the invention provides an enantiomericallyenriched compound of the following formula:

In one specific embodiment the invention provides a compound of formula(IVa)

In one specific embodiment the invention provides a compound of formula(Va)

In one specific embodiment the invention provides a compound of formula(VIa)

In one specific embodiment the invention provides a compound of formula(VIIa):

In one specific embodiment the invention provides a compound of formula(VIIIa):

In one specific embodiment the invention provides a compound of formula(IXa):

In one specific embodiment the invention provides a method of preparinga diol of formula (II);

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₃, R₄,and R₅ are each independently a suitable hydroxy protecting group;comprising: oxidizing a corresponding diene of formula (I);

to provide the diol of formula (II).

In one specific embodiment the invention provides a method for preparingan epoxide of formula (III)

comprising converting a corresponding diol of formula (II);

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₃, R₄,and R₅ are each independently a hydroxy protecting group; to the epoxideof formula (III).

In one specific embodiment the invention provides a method of preparinga compound of formula (IV)

comprising selectively removing R₄ from a corresponding epoxide offormula (III)

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₃, R₄,and R₅ are each independently a hydroxy protecting group to provide anepoxy alcohol, and treating the epoxy alcohol with a suitable acid toprovide a compound of formula (IV).

In one specific embodiment the invention provides a method of preparingan alcohol of formula (V)

comprising selectively removing R₃ from a corresponding compound offormula (IV)

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₃ andR₅ are each independently a hydroxy protecting group.

In one specific embodiment the invention provides a method of preparingan aldehyde of formula (VI)

comprising oxidizing a corresponding alcohol of formula (V)

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₅ is ahydroxy protecting group to provide the aldehyde of formula (VI).

In one specific embodiment the invention provides a method of preparinga stilbene of formula (VII):

wherein R₆ is aryl or heteroaryl optionally substituted with one or morehalo, hydroxy, cyano, CF₃, OCF₃, NR^(a)R^(b), (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl; or (C₂-C₁₅)alkanoyloxy; wherein any(C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy,(C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy of R₆is optionally substituted with one or more halo, hydroxy, cyano, or oxo(═O); comprising reacting a corresponding aldehyde of formula (VI)

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₅ is ahydroxy protecting group with a requisite alkene forming reagent.

In one specific embodiment the invention provides a method for preparinga compound of formula (VIII):

wherein R₆ is aryl or heteroaryl optionally substituted with one or morehalo, hydroxy, cyano, CF₃, OCF₃, NR^(a)R^(b), (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy; wherein any(C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy,(C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy of R₆is optionally substituted with one or more halo, hydroxy, cyano, or oxo(═O); comprising removing the protecting group R₅ from a correspondingcompound of formula (VII):

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₅ is ahydroxy protecting group.

In one specific embodiment the invention provides a method for preparinga diol of formula (IX):

comprising converting a corresponding compound of formula (VIII):

wherein R₁ and R₂ are each independently H or (C₁-C₆)alkyl; and R₆ isaryl or heteroaryl optionally substituted with one or more halo,hydroxy, cyano, CF₃, OCF₃, NR^(a)R^(b), (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl,(C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy; wherein any(C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy,(C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy of R₆is optionally substituted with one or more halo, hydroxy, cyano, or oxo(═O); to the diol.

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

Suitable acids includes any organic acid suitable to catalyze thereaction, such as, trifluoroacetic acid (TFA). Suitable base includesany base suitable to catalyze the reaction, such as, triethyl amine(TEA).

Alkene forming reagent, as used herein, includes any reagent suitable toreact with an aldehyde to form a double bond, such as, an ylide orphosphonate reagent.

As used herein, the terms “isolated” and “purified” refer to substancesthat are substantially free of other biological agents, for example, atleast about 95%, about 98%, or about 99% pure.

As used herein, the term “AD-mix-α,” refers to an asymmetricdihydroxylation chiral ligand system involving two naturally deriveddihydroquinine (DHQD) alkaloid units linked together by a phthalazine(PHAL) linker. The enantiomeric alkaloid does not occur in nature, sothe naturally derived diasteromeric dihydroquinidine (DHQ) basedanalogue is used, (DHQ)₂PHAL, K₃Fe(CN)₆— K₂CO₃ and K₂OsO₄-2H₂O (Firstreported by K. Barry Sharpless (cf. J. Org. Chem., 1992, 57, 2768)). Itis commercially available from Aldrich (licensed from Rhodia-ChirexInc.) The term “AD-mix-α,” includes the related reagent “AD-mix-β.”Other suitable AD-mix-α reagents or alternatives are known to thoseskilled in the art and disclosed in more detail by Corey and Zhang inOrganic Letters, 2001, 3, 3211-3214, and the references cited therein.

As used herein, the terms “treat,” “treatment,” and “treating,” extendto prophylaxis and include prevent, prevention, preventing, lowering,stopping or reversing the progression or severity of the condition orsymptoms being treated. As such, the term “treatment” includes bothmedical, therapeutic, and/or prophylactic administration, asappropriate.

Compounds and pharmaceutical compositions suitable for use in thepresent invention include those wherein the active compound isadministered in an effective amount to achieve its intended purpose.More specifically, a “therapeutically effective amount” means an amounteffective to treat the disease, disorder, and/or condition.Determination of a therapeutically effective amount is well within thecapacity of persons skilled in the art, especially in light of thedetailed disclosure provided herein.

The pharmaceutically active compounds of the invention can be formulatedas pharmaceutical compositions and administered to a mammalian host,such as a human patient in a variety of forms adapted to the chosenroute of administration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid. Useful solid carriers include finelydivided solids such as talc, clay, microcrystalline cellulose, silica,alumina and the like. Useful liquid carriers include water, alcohols orglycols or water-alcohol/glycol blends, in which the present compoundscan be dissolved or dispersed at effective levels, optionally with theaid of non-toxic surfactants. Adjuvants such as fragrances andadditional antimicrobial agents can be added to optimize the propertiesfor a given use. The resultant liquid compositions can be applied fromabsorbent pads, used to impregnate bandages and other dressings, orsprayed onto the affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the pharmaceutically active compounds of the invention to theskin are known to the art; for example, see Jacquet et al. (U.S. Pat.No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat.No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).

Useful dosages of the pharmaceutically active compounds of the inventioncan be determined by comparing their in vitro activity, and in vivoactivity in animal models. Methods for the extrapolation of effectivedosages in mice, and other animals, to humans are known to the art; forexample, see U.S. Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

The compounds of the invention can also be administered in combinationwith other therapeutic agents that are effective to treat cancer.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The anti-cancer activity of a compound of the invention may bedetermined using pharmacological models which are well known to the art,for example, NCI 60-cell line anticancer assay. Representative compoundsof formula (XX) were tested and were found to have anti-cancer activityas illustrated in this assay.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES Example 1 3-Deoxyschweinfurthin B (30, FIG. 3)

To a solution of stilbene 29 (24 mg, 0.04 mmol) in MeOH (2 mL) was addedcamphorsulphonic acid (10 mg, 0.04 mmol). The resulting solution wasstirred at rt for 20 hr, and then heated to 60° C. for an additional 5hr. The reaction was quenched by addition of sat. NaHCO₃, extracted withethyl acetate, and the organic phase was washed with brine and driedover MgSO₄. Concentration in vacuo, followed by final purification bycolumn chromatography (1:1, hexanes:ethyl acetate) afforded3-deoxyschweinfurthin B (30, 16 mg, 79%) as a clear oil: ¹H NMR (CDCl₃)δ 6.83 (m, 4H), 6.55 (s, 2H), 5.31 (s, 1H), 5.28 (t, J=6.9 Hz, 1H), 5.06(m, 1H), 3.88 (s, 3H), 3.43 (m, 3H), 2.72 (d, J=9.1 Hz, 2H), 2.15-2.06(m, 5H), 1.90-1.82 (m, 3H), 1.82 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H),1.25 (s, 3H), 1.10 (s, 3H), 0.88 (s, 3H); ¹³C NMR (CDCl₃) δ 155.2 (2C),148.9, 142.7, 139.2, 137.1, 132.1, 128.8, 128.6, 125.7, 124.2, 122.6,121.4, 120.6, 112.8, 107.0, 106.2 (2C), 78.0, 77.1, 55.0, 46.8, 39.7,38.4, 37.6, 28.3, 27.3, 26.4, 25.7, 23.1, 22.5, 19.8, 17.7, 16.2, 14.3;HRMS (ESI) calcd for C₃₅H₄₆O₅ (M⁺) 546.3345, found 546.3342.

The intermediate stilbene 29 was prepared as follows.

-   a.    3-(3′,7′-Dimethyl-2-octen-6′S,7′-diol)-4-(tert-butyldimethyl-siloxy)-5-methoxy-benzyloxy]-tert-butyldimethylsilane    (21, FIG. 2). To a solution of AD-mix-α (2.41 g) in water/t-BuOH (15    mL, 1:1) was added methanesulfonamide (0.17 g) and the solution was    cooled to −7° C. The geranylated arene 13 (0.89 g, 1.71 mmol) (As    reported by E. Treadwell, et al., Organic Letters, 2002, 4,    3639-3642.) was added via syringe as a neat oil and the solution was    kept at 0° C. for 20 hours, and then allowed to warm to rt and    stirred for an additional 5 days. Solid Na₂SO₃ was added and the    solution was stirred for 1 hour. The solution was extracted with    EtOAc, the resulting organic layer was washed with 2N NaOH and    brine, and then dried (MgSO₄) and concentrated in vacuo to afford a    clear oil. Final purification by column chromatography (1:1    hexanes:ethyl acetate) gave the diol 21 (0.86 g, 92%) as a clear    oil: ¹H NMR δ 6.72 (d, J=2.0 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 5.38    (t, J=7.1 Hz, 1H), 4.64 (s, 2H), 3.77 (s, 3H), 3.35 (d, J=7.3 Hz,    2H), 3.35 (m, 1H), 2.33-2.23 (m, 2H), 2.17-2.00 (m, 2H), 1.70 (s,    3H), 1.66-1.56 (m, 1H), 1.50-1.36 (m, 1H), 1.19 (s, 3H), 1.15 (s,    3H), 1.00 (s, 9H), 0.93 (s, 9H), 0.17 (s, 6H), 0.08 (s, 6H); ¹³C NMR    δ 149.7, 141.3, 135.7, 133.7, 132.1, 123.3, 119.0, 107.3, 78.2,    73.0, 65.0, 54.7, 36.7, 29.7, 28.5, 26.4, 26.1 (3C), 25.9 (3C),    23.2, 21.0, 18.9, 16.2, −3.9 (2C), −5.2 (2C). Anal. Calcd for    C₃₀H₅₆O₅Si₂: C, 65.17; H, 10.21. Found: C, 65.11, H, 10.22.-   b.    4-(tert-Butyldimethylsilyloxy)-5-methoxy-3-(3′,7′-dimethyl-6′-epoxy-2′-octenyl)benzyloxy-tert-butyldimethylsilane    (24, FIG. 3). To a solution of diol 21 (2.03 g, 3.7 mmol), in CH₂Cl₂    (20 mL) at 0° C., was added TEA (1.35 mL, 9.69 mmol) followed 30    minutes later by MsCl (0.43 mL, 5.58 mmol). After 35 minutes the    reaction was allowed to warm to rt, and after a total of 2 hrs a    second aliquot of TEA (0.80 mL, 5.74 mmol) was added and the    reaction was stirred for 30 min. A solution of K₂CO₃ (2.31 g, 16.7    mmol) in MeOH (70 mL) was poured into the vessel and the solution    was allowed to react for 20 hours. After filtration and extraction    of the of the resulting filtrate with ethyl acetate, the combined    organic phase was washed with brine, dried (MgSO₄), and concentrated    under vacuum to afford a white oil. Final purification by flash    chromatography (12:1 hexanes:ethyl acetate) yielded the target    epoxide 24 as a viscous clear oil (1.48 g, 75%): ¹H NMR δ 6.72 (d,    J=1.7 Hz, 1H), 6.65 (d, J=1.6 Hz, 1H), 5.36 (tm, J=7.2 Hz, 1H), 4.64    (s, 2H), 3.77 (s, 3H), 3.34 (d, J=7.1 Hz, 2H), 2.72 (t, J=6.3 Hz,    1H), 2.30-2.10 (m, 2H), 1.70 (s, 3H), 1.75-1.60 (m, 2H), 1.28 (s,    3H), 1.25 (s, 3H), 0.99 (s, 9H), 0.93 (s, 9H), 0.17 (s, 6H), 0.08    (s, 6H); ¹³C NMR δ 149.7, 141.3, 135.0, 133.7, 132.1, 123.3, 119.0,    107.3, 65.0, 64.2, 58.3, 54.7, 36.3, 28.5, 27.4, 26.1 (3C), 26.0    (3C), 24.9, 18.9, 18.7, 18.4, 16.2, −3.9 (2C), −5.2 (2C). Anal.    Calcd for C₃₀H₅₄O₄Si₂: C, 67.36; H, 10.17. Found: C, 67.12; H,    10.28.-   c.    (6′R)-4-Hydroxy-3-methoxy-5-(3′,7′-dimethyl-6′-epoxy-2′-octenyl)-benzyl    alcohol (26, FIG. 3). Silyl ether 24 (840 mg, 1.57 mmol) was    dissolved in THF (70 mL) and the solution was cooled to 0° C. To    this solution was added TBAF (4.6 mL, 1.00 M in THF), the reaction    was allowed to warm to rt and after 1.5 hrs was quenched with sat.    NH₄Cl. After extraction with ethyl acetate, the combined organic    extract was washed with water and brine, dried over MgSO₄, and    concentrated in vacuo to give a yellow oil. Final purification by    flash chromatography (4:1, hexanes:ethyl acetate) gave the diol 26    (352 mg, 96%): ¹H NMR (CDCl₃) δ 6.77 (s, 1H), 6.74 (s, 1H), 5.70 (s,    1H), 5.37 (t, J=7.3 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 3.89, (s, 3H),    3.36 (d, J=7.3 Hz, 2H), 2.71 (t, J=6.2 Hz, 1H), 2.24-2.12 (m, 2H),    1.74 (s, 3H), 1.68-1.62 (m, 3H), 1.27 (s, 3H), 1.25 (s, 3H); ¹³C NMR    (CDCl₃) δ 146.3, 142.8, 135.3, 132.1, 127.0, 122.7, 120.7, 107.5,    65.6, 64.3, 58.4, 56.0, 36.4, 27.8, 27.3, 24.8, 18.7, 16.1. Anal.    Calcd for C₁₈H₂₆O₄.0.5H₂O: C, 68.55; H, 8.63. Found: C, 68.23; H,    8.53.-   d. Diol (27, FIG. 3). To a solution of epoxyphenol 26 (352 mg, 1.2    mmol) in CH₂Cl₂ (40 mL) at 0° C. was added trifluoroacetic acid    (0.26 mL, 3.4 mmol). The resulting solution was allowed to stir 2    hours and Et₃N (1.4 mL, 10.0 mmol) was added. After an additional 30    minutes, water (75 mL) was added, the phases were separated, and the    aqueous phase was extracted with ethyl acetate. The combined organic    phase was washed with water, and brine then dried (MgSO₄), and    concentrated. Final purification by flash chromatography (2:1 to 1:1    hexanes:ethyl acetate) afforded the tricyclic diol 27 (135 mg, 38%)    as a light yellow oil: ¹H NMR (CDCl₃) δ 6.73 (s, 1H), 6.70 (s, 1H),    4.57 (s, 2H), 3.86 (s, 3H), 3.39 (dd, J=11.6, 3.8 Hz, 1H), 2.69 (d,    J=8.9 Hz, 2H), 2.15-2.04 (m, 2H), 1.88-1.59 (m, 6H, 2H exchange with    D₂O), 1.23 (s, 3H), 1.08 (s, 3H), 0.87 (s, 3H); ¹³C NMR (CDCl₃) δ    148.9, 142.1, 132.0, 122.5, 120.4, 108.5, 78.0, 76.8, 65.5, 56.0,    46.7, 38.3, 37.6, 28.3, 27.3, 23.1, 19.7, 14.2; HRMS (ESI) calcd for    C₁₈H₂₆O₄ (M⁺) 306.1831, found 306.1823. Anal. Calcd for    C₁₈H₂₆O₄.0.75H₂O: C, 67.58; H, 8.66. Found: C, 67.96; H, 8.33.-   e. Aldehyde (28, FIG. 3). To a solution of benzylic alcohol 27 (251    mg, 0.82 mmol) in CH₂Cl₂ (30 mL) was added MnO₂ (1.71 g, 19.6 mmol)    as a single aliquot. The resulting suspension was allowed to stir    for 26 hours then filtered through celite and the residue was    concentrated in vacuo to afford the aldehyde 28 as a white solid    (249 mg, 100%): [α]^(25.0) _(D)=+97.8 (c 0.126, CHCl₃); ¹H NMR    (CDCl₃) δ 9.80 (s, 1H), 7.25 (s, 1H), 7.24 (s, 1H), 3.90 (s, 3H),    3.45 (dd, J=11.4, 3.8 Hz, 1H), 2.80-2.77 (m, 2H), 2.22-2.15 (m, 1H),    1.94-1.82 (m, 2H), 1.74-1.61 (m, 2H), 1.28 (s, 3H), 1.13 (s, 3H),    0.91 (s, 3H); ¹³C NMR δ 191.1, 149.5, 148.7, 128.7, 127.3, 122.5,    107.3, 78.4, 77.8, 56.0, 46.5, 38.4, 37.5, 28.2, 27.3, 23.0, 20.0,    14.3. Anal. Calcd for C₁₈H₂₄O₄.1H₂O: C, 67.06; H, 8.13. Found: C,    66.98; H, 8.17.-   f. 3-Deoxy-dimethoxyschweinfurthin B (29, FIG. 3). A suspension of    NaH (29 mg, 1.2 mmol), and 15-crown-5 (4 μL, 0.02 mmol) in THF (1.5    mL) was cooled to 5° C. To this was added aldehyde 28 (10 mg, 0.03    mmol) and phosphonate 5 (22 mg, 0.05 mmol) in THF (2 mL). The    mixture was allowed to warm to rt and stirred a total of 18 hr.    Water was added dropwise, and the solution was extracted with ether.    The resulting organic phase was washed with brine, dried over MgSO₄,    and concentrated in vacuo. Final purification by column    chromatography (3.5:1 to 1:1, hexanes:ethyl acetate) gave the    stilbene 29 (15.2 mg, 80%) as a straw colored oil: ¹H NMR (CDCl₃)    6.95-6.85 (m, 6H), 5.24 (s, 4H), 5.24 (t, 1H,), 5.07 (t, J=11.7 Hz,    1H), 3.89 (s, 3H), 3.50 (s, 6H), 3.40 (m, 3H), 2.72 (d, J=8.7 Hz,    2H), 2.16-1.85 (m, 7H), 1.79 (s, 3H), 1.70-1.65 (m, 3H), 1.65 (s,    3H), 1.57 (s, 3H), 1.26 (s, 3H), 1.10 (s, 3H), 0.89 (s, 3H); ¹³C NMR    (CDCl₃) δ 155.9 (2C), 148.9, 142.5, 136.7, 134.6, 131.2, 128.9,    128.2, 126.4, 124.3, 122.6, 122.5, 120.5, 119.5, 106.8, 105.9 (2C),    94.5 (2C), 78.1, 77.0, 55.9 (2C), 55.9, 46.7, 39.8, 38.4, 37.7,    28.3, 27.3, 26.7, 25.6, 23.1, 22.7, 19.8, 17.6, 16.0, 14.3; HRMS    (ESI) calcd for C₃₉H₅₄O₇ (M⁺) 634.3870, found 634.3871. This    compound is also a compound of the invention.

As shown in FIG. 2, the intermediate diol 21 can be prepared inenantiomerically pure form through formation of the S-mandelate orR-mandelate ester, followed by separation of the resulting diastereomers(e.g. by chromatography) and subsequent hydrolysis. For example seeNeighbors J. D. et al., J. Org. Chem., 2005, 70, 925-931. Details forthe preparation of the mandelate esters is provided below.

-   g. S—O-methyl mandelate (22, FIG. 2). To a solution of diol 21 (33    mg, 0.1 mmol), EDC (19 mg, 0.1 mmol), and DAAP (4 mg, 0.03 mmol), in    CH₂Cl₂ (2 mL) was added S-(+)-O-methyl mandelic acid (12 mg, 0.1    mmol). After 1 hour at rt, water was added and the resulting    solution was extracted with CH₂Cl₂. The combined organic phase was    dried (MgSO₄) and concentrated. Further purification by flash    chromatography (5:1 to 2:1 hexanes:ethyl acetate) afforded the    mandelate ester 22 (25 mg, 60%) as a clear oil, along with a small    amount of the diastereomeric ester (not isolated): [α]^(26.4)    _(D)=+42.1 (c 0.28, CHCl₃); ¹H NMR (CDCl₃) δ 7.46 (dd, J=7.9, 1.8    Hz, 2H), 7.40-7.32 (m, 3H), 6.72 (s, 1H), 6.64 (s, 1H), 5.27 (t,    J=8.0 Hz, 1H), 4.79 (s, 1H), 4.65 (s, 2H), 3.77 (s, 3H), 3.43 (s,    3H), 3.33 (d, J=7.9 Hz, 2H), 1.96 (t, J=8.0 Hz, 2H), 1.78-1.61 (m,    3H), 1.64 (s, 3H), 1.00 (s, 9H), 0.94 (s, 15H), 0.18 (s, 6H), 0.09    (s, 6H); ¹³C NMR δ 170.4, 149.7, 141.3, 136.5, 135.0, 133.7, 132.1,    129.0, 128.7 (2C), 127.2 (2C), 123.1, 119.0, 107.3, 82.6, 80.7,    72.3, 65.0, 57.3, 54.7, 35.0, 28.5, 28.1, 26.1 (3C), 26.0 (3C),    25.9, 24.6, 18.9, 18.4, 16.3, −3.9 (2C), −5.1 (2C); HRMS (ESI) calcd    for C₃₉H₆₄O₇Si₂Na (M+Na)⁺ 723.4088, found 723.4090.-   h. R—O-methyl mandelate (23, FIG. 2). In a manner identical to that    described above for preparation of ester 22, the diol 21 (38 mg,    0.07 mmol), EDC (20 mg, 0.1 mmol), and DMAP (10 mg, 0.08 mmol) were    allowed to react with R-(−)—O-methyl mandelic acid (12 mg, 0.07    mmol). Standard workup and final purification by column    chromatography (5:1 hexanes:ethyl acetate) afforded the target ester    23 (41.5 mg, 82%) as a clear oil along with the R,R-diastereomer    (total yield of 100%). A diastereomeric ratio of 84:16,    corresponding to an initial ee of 68%, was determined by integration    of signals at 5.00 and 5.27 ppm in the ¹H NMR spectrum of the    initial mixture. For diastereomer 23: ¹H NMR δ 7.46 (d, J=8.7 Hz,    2H), 7.36-7.28 (m, 3H), 6.73 (s, 1H), 6.57 (s, 1H), 5.00 (t, J=6.6    Hz, 1H), 4.80 (m, 2H), 4.65 (s, 2H), 3.78 (s, 3H), 3.43 (s, 3H),    3.24 (d, J=6.9 Hz, 2H), 1.60 (m, 5H, 1H exchanges with D₂O), 1.45    (s, 3H), 1.16 (s, 6H), 0.99 (s, 9H), 0.93 (s, 9H), 0.17 (s, 6H),    0.09 (s, 6H); ¹³C NMR δ 170.9, 149.7, 141.3, 136.3, 134.9, 133.6,    132.1, 128.8, 128.6 (2C), 127.1 (2C), 123.0, 119.0, 107.3, 82.7,    80.7, 72.4, 65.1, 57.3, 54.7, 35.4, 28.3, 28.2, 26.6, 26.1 (3C),    26.0 (3C), 24.7, 18.9, 18.4, 16.1, −3.9 (2C), −5.1 (2C); HRFABMS    calcd for C₃₉H₆₄O₇NaSi₂ (M+Na)⁺ 723.4088, found 723.4101.

Example 2 Dimethoxy-3-deoxyschweinfurthin B (34)

A solution of phosphonate 33 (20 mg, 0.04 mmol) and aldehyde 28 (10 mg,0.03 mmol) in THF (1.5 mL) was added to a suspension of NaH (29 mg, 0.71mmol, 60% suspension in oil) and 15C5 (4 μL, 22 nmol) in THF (2.5 mL) at0° C. The resulting mixture was allowed to come to rt and stir for 20hours. The solution was quenched with water, extracted (ether), and thecombined organic layers were washed with brine. The residual organiclayer was dried (MgSO₄), and concentrated in vacuo to give a yellow oil.Final purification by column chromatography (1:1 hexanes:EtOAc) affordedthe target schweinfurthin analog 34 (6.4 mg, 37%) as a clear oil: ¹H NMRδ 6.95-6.88 (m, 4H), 6.67 (s, 2H), 5.19 (t, J=6.8 Hz, 1H), 5.07 (t,J=5.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 6H), 3.46-3.44 (m, 2H), 3.36-3.33(m, 1H), 2.75-2.72 (m, 2H), 2.21-1.75 (m, 9H), 1.77 (s, 3H), 1.65 (s,3H), 1.58 (s, 3H), 1.27 (s, 3H), 1.10 (s, 3H), 0.89 (s, 3H); HREIMScalcd for C₃₇H₅₀O₅ (M⁺) 574.3658, found 574.3651.

The intermediate phosphonate 33 was prepared as follows.

-   a.    [4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dimethoxy-phenyl]-methanol (32)    nBuLi (0.87 mL, 2.15 M in hexanes) was added dropwise to a solution    of benzylic alcohol 31 (105 mg, 0.62 mmol) and TMEDA (0.28 mL, 1.9    mmol) in THF (10 mL) at −20° C. After the solution was stirred at    −20° C. for 1 h, CuBr as its DMS complex (255 mg, 1.24 mmol) was    added in one portion and the solution was stirred for 1 h at −20° C.    Geranyl bromide (0.15 mL, 0.76 mmol) in THF (5 mL) was added via    syringe and the reaction mixture was stirred for 2 h at −20° C. The    reaction was quenched by addition of 1N NH₄Cl, the aqueous layer was    neutralized to pH 7 with 1N HCl, and this layer was extracted with    EtOAc. The combined organic layers were washed with brine, dried    (MgSO₄), and concentrated in vacuo. Final purification of the    residue by flash column chromatography (20% EtOAc in hexanes)    afforded alcohol 32 (76 mg, 40%) as a clear oil. ¹H NMR δ 6.54 (s,    2H), 5.17-5.12 (tm, J=7.1 Hz, 1H), 5.07-5.02 (tm, J=6.9 Hz, 1H),    4.63 (s, 2H), 3.80 (s, 6H), 3.31 (d, J=7 Hz, 2H), 2.04-1.89 (m, 4H),    1.74 (s, 3H), 1.63 (s, 3H), 1.55 (s, 3H); ¹³C NMR δ 160.3 (2C),    141.8, 136.8, 133.2, 126.6, 124.8, 119.9, 104.7 (2C), 68.0, 57.9    (2C), 41.9, 28.9, 27.8, 24.2, 19.8, 18.1. Anal. Calcd for C₁₉H₂₈O₃:    C, 74.96; H, 9.27. Found: C, 74.82; H, 9.34.-   b.    [4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dimethoxy-benzyl]-phosphonic    acid diethyl ester (33) Methanesulfonyl chloride (0.15 mL, 1.94    mmol) was added dropwise to a solution of alcohol 32 (181 mg, 0.59    mmol) and Et₃N (0.3 mL 1.9 mmol) in CH₂Cl₂ (5 mL) and the solution    was stirred for 2 h at 0° C. The reaction mixture was allowed to    warm to rt over 5 h, quenched by addition of H₂O, and extracted with    EtOAc. The combined organic layers were washed with NH₄Cl (sat),    brine, dried (MgSO₄), and concentrated in vacuo. The resulting    residue and NaI (310 mg, 2.06 mmol) were stirred in acetone (8 mL)    for 24 h. The reaction mixture was concentrated in vacuo to afford a    red solid, which was dissolved in EtOAc. After the resulting yellow    solution was washed once with NaHCO₃ and then with Na₂S₂O₃ until the    color faded, it was extracted with ether and the combined organic    layers were dried (MgSO₄) and concentrated in vacuo. The resulting    yellow oil was added to triethyl phosphite (1.5 mL) and the mixture    was heated at 100° C. for 20 h. After the solution was allowed to    cool to rt, it was poured into ether (5 mL). The mixture was    extracted with ether, dried (MgSO₄), and concentrated in vacuo. The    initial yellow oil was purified by flash chromatography (50% EtOAc    in hexanes) to afford phosphonate 33 (73 mg, 40%) as a light yellow    oil: ¹H NMR δ 6.49 (d, J=2.4 Hz, 2H), 5.18-5.13 (tm, J=7.3 Hz, 1H),    5.07-5.02 (tm, J=6.8 Hz, 1H), 4.09-3.98 (m, 4H), 3.80 (s, 6H), 3.31    (d, J=7.0 Hz, 2H), 3.11 (d, J_(PH)=21.5 Hz, 2H), 2.06-1.94 (m, 4H),    1.82 (s, 3H), 1.68 (s, 3H), 1.56 (s, 3H), 1.27 (tm, J=7.0 Hz, 6H);    ¹³C NMR δ 160.9 (d, J_(CP)=3.1 Hz, 2C), 137.5, 134.1, 132.9 (d,    J_(CP)=9.0 Hz), 127.5, 125.7 (d, J_(CP)=2.9 Hz), 120.1 (d,    J_(CP)=3.4 Hz), 108.6 (d, J_(CP)=6.7 Hz, 2C), 65.1 (d, J_(CP)=6.7    Hz, 2C), 58.7 (2C), 42.8, 37.1 (d, J_(CP)=137.3 Hz), 29.7, 28.6,    24.9, 20.6, 19.4 (d, J_(CP)=6.0 Hz, 2C), 18.9; ³¹P NMR δ +26.4; HRMS    (EI) calcd for C₂₃H₃₇O₅PNa [M⁺+Na], 447.2276; found 447.2265.

Example 37-{2-[4-(3,7-Dimethyl-octa-6,7-dienyl)-phenyl]-vinyl}-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol(56)

To a suspension of NaH (64 mg, 1.6 mmol, 60% in mineral oil) in THF (17mL) at 0° C. was added a mixture of phosphonate 43 (56 mg, 0.15 mmol)and aldehyde 28 (28 mg, 0.09 mmol) in THF (3 mL). After 5 min 15C5 (10μL) was added and the reaction was allowed to warm to rt and stir for 19hr. Water was added and the mixture was extracted with ethyl acetate.The combined organic phase was washed with brine and dried (MgSO₄).Concentration in vacuo afforded a yellow oil and final purification bycolumn chromatography (1:1 hexanes:EtOAc) gave the stilbene 56 (26 mg,55%) as a clear oil: ¹H NMR δ 7.40 (m, 2H), 7.16 (m, 2H), 6.95-6.94 (m,2H), 6.89-6.88 (m, 2H), 5.34 (td, J=7.3, 1.0 Hz, 1H), 5.11 (t, J=6.7 Hz,1H), 3.89 (s, 3H), 3.43 (dd, J=11.7, 4.0 Hz, 1H), 3.35 (d, J=7.3 Hz,2H), 2.74-2.71 (m, 2H), 2.16-2.04 (m, 5H), 1.90-1.81 (m, 2H), 1.80-1.70(m, 2H), 1.71 (s, 3H), 1.69 (s, 3H), 1.61 (s, 3H), 1.25 (s, 3H), 1.10(s, 3H), 0.90 (s, 3H); ¹³C NMR δ 148.9, 142.5, 140.9, 136.3, 135.2,131.4, 129.1 (2C), 128.6, 127.8, 126.2, 126.2 (2C), 124.2, 122.8, 122.6,120.4, 106.9, 78.0, 77.0, 56.0, 46.7, 39.7, 38.4, 37.6, 33.9, 28.3,27.3, 26.6, 25.7, 23.1, 19.8, 17.7, 16.1, 14.3; HREIMS calcd forC₃₅H₄₆O₃ (M⁺) 514.3447, found 514.3447.

The intermediate phosphonate 43 was prepared as follows.

-   a.    tert-Butyl-[4-(3,7-dimethyl-octa-2,6-dienyl)-benzyloxy]-dimethyl-silane (40)    nBuLi (7.90 mL, 2.5 M in hexane, 19.8 mmol) was added dropwise to a    stirred solution of aryl bromide 39 (3.13 g, 10.4 mmol) in THF (15    mL) over 15 min at −78° C. The reaction mixture was allowed to stir    for 2 h at −78° C. Geranyl bromide (2.5 mL, 12.6 mmol) was added    dropwise and the reaction mixture was stirred for 2 h at −78° C. The    reaction mixture was allowed to warm to rt, was quenched by addition    of H₂O, and then was extracted with ether. The combined organic    layers were washed with NH₄Cl (sat), brine, dried (MgS₄), and    concentrated in vacuo. Final purification of the residue by flash    column chromatography (hexanes) afforded compound 40 (2.61 g, 70%)    as a light yellow oil: ¹H NMR δ 7.24-7.19 (m, 2H), 7.14-7.12 (m,    2H), 5.43-5.38 (tm, J=7.4 Hz, 1H), 5.20-5.15 (tm, J=7.5 Hz, 1H),    4.77 (s, 2H), 3.41 (d, J=7.4 Hz, 2H), 2.19-2.09 (m, 4H), 1.77 (s,    3H), 1.75 (s, 3H), 1.67 (s, 3H), 1.01 (s, 9H), 0.16 (s, 6H); ¹³C NMR    δ. 140.6, 140.0, 136.3, 131.6, 128.4 (2C), 126.4 (2C), 124.5, 123.4,    65.1, 39.9, 34.1, 26.8, 26.2 (3C), 25.9, 18.6, 17.9, 16.3, −5.0    (2C). Anal. Calcd for C₂₃H₃₈OSi: C, 77.01; H, 10.68. Found: C,    77.08; H, 10.69.-   b. [4-(3,7-Dimethyl-octa-2,6-dienyl)-phenyl]-methanol (41) TBAF    (26.0 mL, 1.0 M in THF, 26.0 mmol) was added dropwise to a stirred    solution of protected alcohol 40 (2.56 g, 7.14 mmol) in THF (20 mL).    The solution was stirred for 2 h at 0° C. and then was allowed to    warm to rt over 5 h. The reaction was quenched by addition of NH₄Cl    (sat), and extracted with EtOAc. The combined organic layers were    washed with brine, dried (MgSO₄), and concentrated in vacuo. Final    purification of the residue by flash column chromatography (20%    EtOAc in hexanes) afforded compound 41 (1.35 g, 77%) as a light    yellow oil: ¹H NMR δ 7.28-7.24 (m, 2H), 7.18-7.15 (m, 2H), 5.35-5.30    (tm, J=7.2 Hz, 1H), 5.12-5.08 (tm, J=6.7 Hz, 1H), 4.63 (s, 2H), 3.35    (d, J=7.3 Hz, 2H), 2.12-2.02 (m, 4H), 1.70 (s, 1H exchanges with    D₂O), 1.70 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H); ¹³C NMR δ 141.6,    138.5, 136.5, 131.7, 128.7 (2C), 127.4 (2C), 124.4, 123.1, 65.4,    39.9, 34.1, 26.8, 26.0, 17.9, 16.3; HRMS (EI) calcd for C₁₇H₂₄O    [M⁺], 244.1827; found 244.1832.-   c. 1-(3,7-Dimethyl-octa-2,6-dienyl)-4-iodomethyl-benzene (42)    Methanesulfonyl chloride (1.8 mL, 23.3 mmol) was added dropwise to a    stirred solution of alcohol 41 (1.27 g, 5.22 mmol) and Et₃N (3 mL    21.5 mmol) in CH₂Cl₂ (20 mL) at 0° C. over 2 h. The reaction mixture    was allowed to warm to rt over 5 h. After the reaction was quenched    by addition of water, it was extracted with EtOAc. The combined    organic layers were washed with NH₄Cl (sat), brine, dried (MgSO₄),    and concentrated in vacuo. The resulting yellow residue was treated    with NaI (3.51 g, 23.4 mmol) in acetone (20 mL) at rt for 24 h. The    reaction mixture was concentrated in vacuo to afford a red solid,    which was dissolved in EtOAc. After the resulting solution was    washed once with NaHCO₃ and then with Na₂S₂O₃ until the color faded,    the aqueous layer was extracted with ether and the combined organic    layers were dried (MgSO₄) and concentrated in vacuo. Final    purification of the residue by flash column chromatography (20%    EtOAc in hexanes) afforded compound 42 (1.44 g, 78%) as a yellow    oil: ¹H NMR δ 7.30-7.24 (m, 2H), 7.11-7.08 (m, 2H), 5.35-5.30 (tin,    J=7.2 Hz, 1H), 5.14-5.09 (tin, J=6.6 Hz, 1H), 4.47 (s, 2H), 3.33 (d,    J=7.2 Hz, 2H), 2.14-2.03 (m, 4H), 1.71 (s, 6H), 1.61 (s, 3H); ¹³C    NMR δ. 141.9 (2C), 136.8, 131.7, 129.0 (2C), 128.9 (2C), 124.4,    122.8, 39.9, 34.1, 26.8, 26.0, 17.9, 16.3, 6.4; HRMS (EI) calcd for    C₁₇H₂₃ [M⁺−I], 227.1800; found 227.1801.-   d. Diethyl[4-(3,7-dimethyl-octa-2,6-dienyl)-benzyl]phosphonate (43)

A stirred solution of iodide 42 (1.35 g, 3.82 mmol) in triethylphosphite (25 mL) was heated at reflux for 4 h, and then allowed to coolto rt. Excess triethyl phosphite was removed by vacuum distillation andthe resulting yellow oil was purified by flash chromatography (30% EtOAcin hexanes) to afford phosphonate 43 (1.34 g, 97%) as a light yellowoil: ¹H NMR δ 7.22-7.18 (m, 2H), 7.12-7.09 (m, 2H), 5.33-5.29 (tm, J=7.2Hz, 1H), 5.11-5.08 (tm, J=6.6 Hz, 1H), 4.06-4.00 (m, 4H), 3.32 (d, J=7.2Hz, 2H), 3.11 (d, J_(PH)=21.3 Hz, 2H), 2.12-2.05 (m, 4H), 1.69 (s, 3H),1.68 (s, 3H), 1.60 (s, 3H), 1.24 (t, J=7.2 Hz, 6H); ¹³C NMR δ 140.6 (d,J_(CP)=3.8 Hz), 136.5, 131.7, 129.8 (d, J_(CP)=6.5 Hz, 2C), 128.9 (d,J_(CP)=9.3 Hz), 128.7 (d, J_(CP)=3.1 Hz, 2C), 124.5, 123.1, 62.2 (d,J_(CP)=6.8 Hz, 2C), 39.9, 34.4, 32.6 (d, J_(CP)=138.2 Hz), 26.8, 26.0,17.9, 16.6 (d, J_(CP)=6.1 Hz, 2C), 16.3; ³¹P NMR δ +26.6. Anal. Calcdfor C₂₁H₃₃O₃P: C, 69.21; H, 9.13. Found: C, 69.09; H, 9.16.

Example 47-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-difluoro-phenyl]-vinyl}-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol(57)

To a stirred suspension of NaH (30 mg, 1.3 mmol) and 15C5 (5 μL, 3 mol%) in THF (5 mL) was added phosphonate 46 (71 mg, 0.177 mmol) andaldehyde 28 (20 mg, 0.066 mmol) at 0° C. and the solution was allowed towarm to rt over 10 h. The reaction was quenched by addition of water andthen was extracted with EtOAc. The combined organic layers were washedwith brine, dried (MgSO₄), and concentrated in vacuo. Final purificationof the residue by flash column chromatography (50% EtOAc in hexanes)afforded compound 57 (30.9 mg, 85%) as a clear oil: ¹H NMR δ 6.99-6.79(m, 6H), 5.26-5.22 (tm, J=7.0 Hz, 1H), 5.09-5.04 (tm, J=6.8 Hz, 1H), 3.9(s, 3H), 3.47-3.42 (m, 1H), 3.37-3.35 (dm, J=7.2 Hz, 2H), 2.77-2.74 (m,1H), 2.73-2.70 (m, 1H), 2.18-1.82 (m, 7H), 1.76 (s, 3H), 1.72-1.69 (m,2H), 1.65 (s, 3H), 1.58 (s, 3H), 1.27 (s, 3H), 1.09 (s, 3H), 0.90 (s,3H); ¹³C NMR δ 163.4-160.0 (dd, J_(CF)=241.8 Hz, J_(CF)=9.8 Hz, 2C),149.3, 143.4, 137.9, 136.8, 131.7, 130.5, 124.5 (t, J_(CF)=9.5 Hz),124.3, 123.0, 121.1, 120.8, 115.9 (t, J_(CF)=23.4 Hz), 110.0, 108.7 (dd,J_(CF)=26.6 Hz, J_(CF)=8.6 Hz, 2C), 107.3, 78.2, 77.4, 56.3, 47.0, 39.8,38.6, 37.9, 28.5, 27.6, 26.7, 25.8, 23.4, 21.6 (t, J_(CF)=2.0 Hz), 20.1,17.8, 16.2, 14.5; HRMS (EI) calcd for C₃₅H₄₄O₃F₂ [M⁺], 550.3259; found550.3256.

The intermediate phosphonate 46 was prepared as follows.

-   a.    [4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-difluoro-phenyl]-methanol (45)    A solution of benzylic alcohol 44 (67 mg, 0.46 mmol) and TMEDA (0.21    mL, 1.4 mmol) in THF (10 mL) was cooled to −20° C. After nBuLi (0.64    mL, 2.15 M in hexanes) was added dropwise and the solution was    stirred at −20° C. for 1 h, CuBr as its DMS complex (192 mg, 0.93    mmol) was added in one portion and the solution was stirred for 1 h    at −20° C. A solution of geranyl bromide (0.11 mL, 0.55 mmol) in THF    (5 mL) was added to the reaction mixture via syringe at −20° C. and    the solution was stirred for 2 h. The reaction was quenched by    addition of 1N NH₄Cl, the aqueous layer was neutralized to pH 7 with    1N HCl, and then was extracted with EtOAc. The combined organic    layers were washed with brine, dried (MgSO₄), and concentrated in    vacuo. Purification by flash column chromatography (20% EtOAc in    hexanes) afforded alcohol 45 (68 mg, 53%) as a clear oil: ¹H NMR δ    6.91-6.83 (dm, J_(HF)=7.5 Hz, 2H), 5.23-5.19 (tm, J=7.3 Hz, 1H),    5.08-5.03 (tm, J=6.8 Hz, 1H), 4.65 (d, J=5.6 Hz, 2H, becomes a    singlet at D₂O wash), 3.36 (d, J=7.2 Hz, 2H), 2.07-1.96 (m, 4H),    1.75 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H); ¹³C NMR δ 161.6 (dd,    J_(CF)=246.9, 9.6 Hz, 2C), 141.2 (t, J_(CF)=9.0 Hz), 136.8, 131.7,    124.3, 120.7, 116.4 (t, J_(CF)=20.9 Hz), 109.4 (dd, J_(CF)=26.6, 8.9    Hz, 2C), 54.4 (t, J_(CF)=2.1 Hz), 39.8, 26.7, 25.9, 21.5 (t,    J_(CF)=2.5 Hz), 17.9, 16.2; HRMS (EI) calcd for C₁₇H₂₂F₂O [M⁺],    280.1639; found 280.1639.-   b. [4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-difluoro-benzyl]-phosphonic    acid diethyl ester (46) PBr₃ (0.03 mL, 0.32 mmol) was added dropwise    to a solution of alcohol 45 (180 mg, 0.64 mmol) in ether (10 mL) and    the solution was stirred for 7 h at 0° C. The reaction mixture was    poured into ice water, extracted with ether, and washed with brine.    The combined organic layer was dried (MgSO₄), and concentrated in    vacuo. The resulting yellow oil was added to triethyl phosphite (3    mL) and sodium iodide (62 mg, 0.41 mmol), and the mixture was heated    at 100° C. for 30 h. After this solution was allowed to cool to rt,    it was poured into ether (10 mL) and washed with sodium thiosulfate.    The mixture was extracted with ether, dried (MgSO₄), and    concentrated in vacuo. The initial yellow oil was purified by flash    chromatography (gradient, 30-80% EtOAc in hexanes) to afford    phosphonate 46 (153 mg, 60%) as a light yellow oil: ¹H NMR δ    6.84-6.77 (m, 2H), 5.22-5.17 (tm, J=6.4 Hz, 1H), 5.08-5.03 (tm,    J=6.9 Hz, 1H), 4.11-4.00 (m, 4H), 3.35-3.32 (dm, J=7.2 Hz, 2H),    3.11-3.04 (dm, J_(PH)=21.7 Hz, 2H), 2.07-1.92 (m, 4H), 1.74 (s, 3H),    1.65 (s, 3H), 1.58 (s, 3H), 1.31-1.24 (tin, J=7.1 Hz, 6H); ¹³C NMR δ    161.4 (ddd, J_(CF)=245.7, 10.0 Hz, J_(CP)=3.5 Hz, 2C), 136.8,    132.0-131.6 (m), 131.7, 124.3, 120.7, 116.0 (td, J_(CF)=20.3 Hz,    J_(CP)=3.5 Hz), 112.9-112.5 (m, 2C), 65.5 (d, J_(CP)=6.75 Hz, 2C),    39.8, 33.5 (dd, J_(CP)=139.2 Hz, J_(CF)=1.9 Hz), 26.7, 25.9, 21.4    (t, J_(CF)=1.7 Hz), 17.9, 16.6 (d, J_(CP)=6.00 Hz, 2C), 16.1; ³¹P    NMR δ +24.8 (t, J_(PF)=2.3 Hz). Anal. Calcd for C₂₁H₃₁F₂O₃P: C,    62.99; H, 7.80. Found: C, 63.22; H, 7.98.

Example 55-Methoxy-1,1,4a-trimethyl-7-styryl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol(59)

To a suspension of NaH (26 mg, 1 mmol) and 15C5 (5 mL, 3 mol %) in THF(5 mL) was added phosphonate 43 (25 mg, 0.12 mmol) and aldehyde 28 (15.8mg, 0.05 mmol) at 0° C. and the reaction mixture was stirred for 10 h atrt. The reaction was quenched by addition of water and extracted withEtOAc. The combined organic layers were washed with brine, dried(MgSO₄), and concentrated in vacuo. Final purification of the residue byflash column chromatography (35% EtOAc in hexanes) afforded compound 59(17 mg, 90%) as a clear oil: ¹H NMR δ 7.50-7.47 (m, 2H), 7.37-7.34 (m,2H), 7.26-7.20 (m, 1H), 6.98 (d, J=8.5 Hz, 2H), 6.91-6.87 (m, 2H), 3.90(s, 3H), 3.46-3.41 (m, 1H), 2.77-2.75 (m, 1H), 2.72-2.68 (m, 2H),2.16-2.11 (m, 1H), 1.90-1.81 (m, 2H), 1.74-1.55 (m, 3H), 1.26 (s, 3H),1.11 (s, 3H), 0.89 (s, 3H); ¹³C NMR δ 149.2, 142.9, 137.9, 129.2, 128.9(2C), 128.8, 127.4, 126.5, 126.4 (2C), 122.9, 120.8, 107.2, 78.2, 77.3,56.3, 47.0, 38.6, 37.9, 28.5, 27.6, 23.4, 20.1, 14.5; HRMS (EI) calcdfor C₂₅H₃₀O₃ [M⁺], 378.2195; found 378.2195.

Example 65-[2-(7-Hydroxy-4-methoxy-8,8,10a-trimethyl-5,7,8,8a,9,10a-hexahydro-6H-xanthen-2-yl)-vinyl]-benzene-1,3-diol(60)

To a stirred solution of stilbene 54 (30 mg, 0.06 mmol) in methanol (5mL) was added CSA (20 mg, 0.09 mmol) and the solution was allowed tostir 10 h at 50° C. The reaction mixture was allowed to cool to rt,concentrated in vacuo, and the residue was dissolved in EtOAc and water.The mixture was extracted with ether, washed with brine, dried (MgSO₄),and concentrated in vacuo. Final purification of the residue by flashcolumn chromatography (60% EtOAc in hexanes) afforded compound 60 (23mg, 93%) as a clear oil: ¹H NMR (CDCl₃/CD₃OD) δ 7.06-6.88 (m, 4H), 6.58(d, J=2.0 Hz, 2H), 6.31 (t, J=2.0 Hz, 1H), 3.97 (s, 3H), 3.75-3.68 (m,1H), 2.96-2.81 (m, 2H), 2.20-1.68 (m, 5H), 1.33 (s, 3H), 1.16 (s, 3H),0.97 (s, 3H); ¹³C NMR (CDCl₃/CD₃OD) δ 157.7 (2C), 148.3, 142.0, 139.4,128.8, 128.0, 125.9, 122.3, 120.3, 106.6, 104.3 (2C), 101.2, 77.0, 76.7,55.1, 46.9, 37.8, 37.2, 27.2, 26.2, 22.5, 18.9, 13.4; HRMS (EI) calcdfor C₂₅H₃₀O₅ [M⁺], 410.2093; found 410.2093.

The intermediate stilbene 54 was prepared as follows.

-   a. (3,5-bis-Methoxymethoxy-benzyl)-phosphonic acid diethyl ester    (37). Methanesulfonyl chloride (1.4 mL, 18.1 mmol) was added    dropwise to a stirred solution of alcohol 35 (881 mg, 3.9 mmol) and    Et₃N (2.2 mL 15.76 mmol) in CH₂Cl₂ (150 mL). The solution was    stirred for 2 h at 0° C. The reaction mixture was allowed to warm to    rt over 5 h, quenched by addition of water, and extracted with    EtOAc. The combined organic layers were washed with NH₄Cl (sat),    brine, dried (MgSO₄), and concentrated in vacuo. The yellow residue    was treated with NaI (2.33 g, 15.6 mmol) in acetone (20 mL) for 24 h    at rt. The reaction mixture was concentrated in vacuo to a red    solid, which was dissolved in EtOAc. After the resulting yellow    solution was washed once with NaHCO₃ and then with Na₂S₂O₃ until the    color faded, it was extracted with ether and the combined organic    layers were dried (MgSO₄) and concentrated in vacuo. Final    purification of the residue by flash column chromatography (30%    EtOAc in hexanes) afforded compound iodide (1.12 g, 84%) as a yellow    oil: ¹H NMR δ 6.73 (d, J=2.2 Hz, 2H), 6.63 (t, J=2.2 Hz, 1H), 5.2    (s, 4H), 4.4 (s, 2H), 3.5 (s, 6H); ¹³C NMR δ 158.5 (2C), 141.5,    110.3 (2C), 104.7, 94.7 (2C), 56.3 (2C), 5.5; HRMS (EI) calcd for    C₁₁H₁₅O₄I [M⁺], 338.0015; found 338.0016. A stirred solution of this    iodide (1.11 g, 3.3 mmol) in triethyl phosphite (2.5 mL) was heated    at reflux for 9 h, then it was allowed to cool to rt and poured into    ether (8 mL). The resulting mixture was extracted with ether, dried    (MgSO₄) and concentrated in vacuo. Final purification of the residue    by flash chromatography (gradient, 30-80% EtOAc in hexanes) afforded    phosphonate 37 (734 mg, 64%) as a light yellow oil: ¹H NMR δ    6.58-6.55 (m, 3H), 5.06 (s, 4H), 3.97 (m, 4H), 3.39 (s, 6H), 3.01    (d, J_(PH)=21.6 Hz, 2H), 1.20 (tm, J=7.1 Hz, 6H); ¹³C NMR δ 158.2    (d, J_(CP)=3.2 Hz, 2C), 133.8 (d, J_(CP)=8.8 Hz), 111.2 (d,    J_(CP)=6.5 Hz, 2C), 103.5 (d, J_(CP)=3.4 Hz), 94.4 (2C), 62.1 (d,    J_(CP)=6.6 Hz, 2C), 55.9 (2C), 33.9 (d, J_(CP)=138.1 Hz), 16.3 (d,    J_(CP)=6.1 Hz, 2C); ³¹P NMR δ+25.7. Anal. Calcd for C₁₅H₂₅O₇P: C,    51.72; H, 7.23. Found: C, 51.55; H, 7.27.-   b.    7-[2-(3,5-bis-Methoxymethoxy-phenyl)-vinyl]-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (54)    To a stirred suspension of NaH (30 mg, 1.3 mmol) and 15C5 (5 μL, 3    mol %) in THF (5 mL) was added phosphonate 37 (25 mg, 0.12 mmol) and    aldehyde 28 (20 mg, 0.066 mmol) at 0° C. The reaction mixture was    allowed to warm to rt over 10 h. The reaction was quenched by    addition of water, and extracted with EtOAc. After the combined    organic layers were washed with brine, dried (MgSO₄), and    concentrated in vacuo, final purification by flash column    chromatography (50% EtOAc in hexanes) afforded compound 54 (30 mg,    91%) as a clear oil: ¹H NMR δ 7.00 (d, J=17.1 Hz, 1H), 6.90-6.85 (m,    5H), 6.64 (t, J=2.1 Hz, 1H), 5.20 (s, 4H), 3.90 (s, 3H), 3.51 (s,    6H), 3.46-3.42 (m, 1H), 2.76-2.74 (m, 1H), 2.73-2.71 (m, 1H),    2.17-2.11 (m, 1H), 1.91-1.81 (m, 2H), 1.75-1.54 (m, 2H), 1.27 (s,    3H), 1.12 (s, 3H), 0.90 (s, 3H); ¹³C NMR δ 158.7 (2C), 149.2, 143.0,    140.1, 129.6, 128.9, 126.2, 122.8, 120.9, 107.8 (2C), 107.3, 104.1,    94.7 (2C), 78.2, 77.3, 55.3 (2C), 56.2, 46.9, 38.6, 37.9, 28.5,    27.6, 23.4, 20.1, 14.5; HRMS (EI) calcd for C₂₉H₃₈O₇ [M⁺], 498.2618;    found 498.2608. This compound is also a compound of the invention.

Example 72-(8-Hydroxy-3,7-dimethyl-octa-2,6-dienyl)-5-[2-(7-hydroxy-4-methoxy-8,8,10a-trimethyl-5,7,8,8a,9,10a-hexahydro-6H-xanthen-2-yl)-vinyl]-benzene-1,3-diol(62)

CSA (20 mg, 0.09 mmol) was added to a stirred solution of stilbene 58(17 mg, 0.026 mmol) in methanol (5 mL) and the reaction mixture wasallowed to stir for 15 h at 50° C. The reaction mixture was allowed tocool to rt, and concentrated in vacuo and the residue was dissolved inEtOAc and water. The mixture was extracted with ether, the organic layerwas washed with brine, dried (MgSO₄), and concentrated in vacuo.Purification of the residue by flash column chromatography (80% EtOAc inhexanes) afforded compound 62 (6 mg, 42%) as a clear oil: ¹H NMR δ6.94-6.73 (m, 4H), 6.49 (s, 2H), 5.40 (s, 2H, exchangeable with D₂O),5.31-5.29 (m, 2H), 4.01 (s, 2H), 3.89 (s, 3H), 3.45-3.43 (m, 3H),2.74-2.72 (m, 1H), 2.72-2.70 (m, 1H), 2.37-2.12 (m, 5H), 1.91-1.57 (m,10H), 1.46 (s, 1H, exchangeable with D₂O), 1.26 (s, 3H), 1.12 (s, 3H),0.90 (s, 3H); ¹³C NMR δ 155.2 (2C), 149.2, 142.9, 139.2, 137.6, 136.5,129.0 (2C), 125.8, 125.0, 122.9, 122.7, 120.8, 112.6, 107.2, 106.4 (2C),78.1, 69.1, 56.2, 47.0, 39.4, 38.6, 37.9, 28.4, 27.6 (2C), 25.1, 23.4,22.7, 20.1, 15.8, 14.5, 13.9; HRMS (EI) calcd for C₃₅H₄₆O₆ [M⁺],561.3216; found 561.3214.

The intermediate stilbene 58 was prepared as follows.

-   a.    {4-[8-(tert-butyl-diphenyl-silanyloxy)-3,7-dimethyl-octa-2,6-dienyl]-3,5-bis-methoxymethoxy-phenyl}-methanol (49)    PBr₃ (0.7 mL, 7.4 mmol) was added dropwise to a solution of alcohol    47 (521 mg, 1.27 mmol) in ether (10 mL) and the solution was stirred    for 7 h at 0° C. The reaction mixture was poured into ice water,    extracted with ether, and washed with brine. The combined organic    layer was dried (MgSO₄), and concentrated in vacuo to give a yellow    residue, bromide 48. A solution of benzylalcohol 35 (305 mg, 1.34    mmol) in THF (5 mL) was added to a stirred suspension of KH (87 mg,    2.2 mmol) in THF (10 mL) and the reaction mixture was stirred for 1    h at 0° C. After TMEDA (0.4 mL, 2.7 mmol) was added, the solution    was cooled to −20° C., then nBuLi (1.87 mL, 2.15 M in hexanes) was    added dropwise and the solution was stirred at −20° C. for 1 h. CuBr    as its DMS complex (556 mg, 2.7 mmol) was added in one portion and    the solution was stirred for 1 h at −20° C. Bromide 48 in THF (5 mL)    was added to the reaction mixture via syringe at −20° C. After 2 h,    the reaction was quenched by addition of 1N NH₄Cl, and the aqueous    layer was neutralized to pH 7 with 1N HCl, and extracted with EtOAc.    The combined organic layer was washed with brine, dried (MgSO₄), and    concentrated in vacuo. Final purification by flash column    chromatography (20% EtOAc in hexanes) afforded compound 49 (341 mg,    43% from alcohol 47) as a clear oil: ¹H NMR δ 7.70-7.67 (m, 4H),    7.43-7.35 (m, 6H), 6.79 (s, 2H), 5.43-5.39 (tm, J=7.0 Hz, 1H),    5.26-5.19 (m, 5H), 4.62 (s, 2H), 4.03 (s, 2H), 3.47 (s, 6H), 3.40    (d, J=9 Hz, 2H), 2.19-1.96 (m, 4H), 1.81 (s, 3H), 1.59 (s, 3H), 1.06    (s, 9H); ¹³C NMR δ 156.0 (2C), 140.2, 135.8 (4C), 134.8, 134.2 (2C),    134.1, 129.7 (2C), 127.8 (4C), 124.6, 122.9, 119.6, 106.7 (2C), 94.6    (2C), 69.3, 65.7, 56.2 (2C), 39.8, 27.1 (3C), 26.4, 22.8, 19.5,    16.3, 13.7. Anal. Calcd for C₃₇H₅₀O₆Si: C, 71.81; H, 8.14. Found: C,    71.72; H, 7.98.-   b.    tert-Butyl-[8-(4-iodomethyl-2,6-bis-methoxymethoxy-phenyl)-2,6-dimethyl-octa-2,6-dienyloxy]-diphenyl-silane (50)    Methanesulfonyl chloride (0.1 mL, 1.3 mmol) was added dropwise to a    stirred solution of alcohol 49 (364 mg, 0.62 mmol) and Et₃N (0.2 mL    1.4 mmol) in CH₂Cl₂ (5 mL) and the solution was stirred for 2 h at    0° C. The reaction mixture was allowed to warm to rt over 5 h,    quenched by addition of H₂O, and extracted with EtOAc. The combined    organic layers were washed with NH₄Cl (sat) and brine, dried    (MgSO₄), and concentrated in vacuo. The resulting yellow residue was    allowed to react with NaI (132 mg, 0.886 mmol) in acetone (8 mL) for    24 h at rt. The reaction mixture was concentrated in vacuo to afford    a red solid, which was dissolved in EtOAc. After the resulting    yellow solution was washed once with NaHCO₃ and then with Na₂S₂O₃    until the color faded, it was extracted with ether and the combined    organic layers were dried (MgSO₄) and concentrated in vacuo. Final    purification by flash column chromatography (30% EtOAc in hexanes)    afforded the iodide 50 (347 mg, 77%) as a yellow oil: ¹H NMR δ    7.77-7.72 (m, 4H), 7.49-7.38 (m, 6H), 6.84 (s, 2H), 5.48-5.44 (tm,    J=6.6 Hz, 1H), 5.29-5.19 (tm, J=6.0 Hz, 1H), 5.20 (s, 4H), 4.43 (s,    2H), 4.08 (s, 2H), 3.50 (s, 6H), 3.41 (d, J=7.1 Hz, 2H), 2.30-2.01    (m, 4H), 1.85 (s, 3H), 1.63 (s, 3H), 1.11 (s, 9H); ¹³C NMR δ 155.8    (2C), 138.1, 135.7 (4C), 134.9, 134.1 (2C), 134.0, 129.7 (2C), 127.8    (4C), 124.5, 122.6, 120.2, 108.6 (2C), 94.6 (2C), 69.2, 56.2 (2C),    39.8, 27.0 (3C), 26.3, 22.9, 19.5, 16.3, 13.7, 6.7; HRMS (EI) calcd    for C₃₇H₄₉IO₅Si [M⁺], 728.2394; found 728.2395.-   c.    {4-[8-(tert-Butyl-diphenyl-silanyloxy)-3,7-dimethyl-octa-2,6-dienyl]-3,5-bis-methoxymethoxy-benzyl}-phosphonic    acid diethyl ester (51) A solution of iodide 50 (68 mg, 0.093 mmol)    and sodium iodide (39 mg, 0.26 mmol) in triethyl phosphite (1.5 mL)    was heated at 100° C. for 20 h, allowed to cool to rt, and poured    into ether (5 mL). The resulting mixture was extracted with ether,    dried (MgSO₄), and concentrated in vacuo. The initial yellow oil was    purified by flash chromatography (50% EtOAc in hexanes) to afford    phosphonate 51 (63.5 mg, 92%) as light yellow oil: ¹H NMR δ    7.70-7.67 (m, 4H), 7.42-7.34 (m, 6H), 6.70 (d, J_(HP)=2.3 Hz, 2H),    5.42-5.39 (tm, J=5.7 Hz, 1H), 5.21-5.17 (trm, J=7.0 Hz, 1H), 5.17    (s, 4H), 4.10-4.00 (m, 6H), 3.45 (s, 6H), 3.37 (d, J=7.0 Hz, 2H),    3.09 (d, J_(PH)=21.5 Hz, 2H), 2.14-1.95 (m, 4H), 1.80 (s, 3H), 1.58    (s, 3H), 1.28 (trm, J=7.08 Hz, 6H), 1.06 (s, 9H); ¹³C NMR δ 155.8    (d, J_(CP)=3.2 Hz, 2C), 135.8 (4C), 134.7, 134.1 (2C), 134.0, 130.5    (d, J_(CP)=9.0 Hz), 129.7 (2C), 127.7 (4C), 124.7, 123.0, 118.9 (d,    J_(CP)=3.9 Hz), 109.8 (d, J_(CP)=6.6 Hz, 2C), 94.6 (2C), 69.2, 62.3    (d, J_(CP)=6.7 Hz, 2C), 56.2 (2C), 39.8, 34.1 (d, J_(CP)=138.3 Hz),    27.0 (3C), 26.5, 22.7, 19.5, 16.6 (d, J_(CP)=5.8 Hz, 2C), 16.3,    13.6; ³¹P NMR δ +26.2. Anal. Calcd for C₄₁H₅₉O₈PSi: C, 66.64; H,    8.05. Found: C, 66.58; H, 8.32.-   d.    [4-(8-Hydroxy-3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-benzyl]-phosphonic    acid diethyl ester (52) TBAF (0.3 mL, 1M in THF, 0.3 mmol) was added    to a solution of phosphonate 51 (55.1 mg, 0.075 mmol) in THF (3 mL)    and the solution was stirred for 3 h at rt. The reaction was    quenched by addition of water and EtOAc, and then extracted with    EtOAc. The combined organic layer was washed with brine, dried    (MgSO₄), and concentrated in vacuo. Final purification of the    residue by flash column chromatography (gradient, 60-100% EtOAc in    hexanes) afforded compound 52 (36 mg, 96%) as a clear oil: ¹H NMR δ    6.66 (broad s, 2H), 5.30-5.24 (m, 1H), 5.13-5.06 (m, 5H), 4.04-3.97    (m, 4H), 3.83 (s, 2H), 3.42 (s, 6H), 3.32 (d, J=7.0 Hz, 2H), 3.04    (d, J_(PH)=21.5 Hz, 2H), 2.07-1.95 (m, 4H), 1.73 (s, 3H), 1.53 (s,    3H), 1.24 (trm, J=6.8 Hz, 6H); ¹³C NMR δ 155.8 (d, J_(CP)=3.4 Hz,    2C), 135.1, 134.1, 130.4 (d, J_(CP)=9.1 Hz), 125.9, 123.4, 119.1 (d,    J_(CP)=3.9 Hz), 109.9 (d, J_(CP)=6.6 Hz, 2C), 94.7 (2C), 68.9, 62.3    (d, J_(CP)=6.7 Hz, 2C), 56.2 (2C), 39.5, 34.0 (d, J_(CP)=138.3 Hz),    26.1, 22.7, 16.6 (d, J_(CP)=6.1 Hz, 2C), 16.2, 13.8; ³¹P NMR δ    +26.2; HRMS (EI) calcd for C₂₅H₁₄O₈P [M⁺], 500.2539; found 500.2531.-   e. 7-{2-[4-(8-Hydroxy-3,7-dimethyl-octa-2,6-dienyl)-3,5-bis    methoxymethoxy-phenyl]-vinyl}-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (58)    To a suspension of NaH (12 mg, 0.3 mmol) and 15C5 (5 mL, 3 mol %) in    THF (5 mL) was added phosphonate 52 (34 mg, 0.068 mmol) and aldehyde    28 (16 mg, 0.053 mmol) at 0° C. and the reaction mixture was allowed    to warm to rt over 10 h. The reaction was quenched by addition of    water and extracted with EtOAc. The combined organic layers were    washed with brine, dried (MgSO₄), and concentrated in vacuo.    Purification of the resulting oil by flash column chromatography    (50% EtOAc in hexanes) afforded compound 58 (20.5 mg, 60%) as a    clear oil: ¹H NMR δ 6.99-6.87 (m, 6H), 5.37-5.33 (tm, J=6.0 Hz, 1H),    5.24-5.18 (m, 5H), 3.95 (s, 2H), 3.91 (s, 3H), 3.52-3.39 (m, 9H),    2.74-2.72 (m, 1H), 2.72-2.70 (m, 1H), 2.17-1.98 (m, 5H), 1.90-1.57    (m, 10H), 1.26 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); ¹³C NMR δ 156.1    (2C), 149.2, 142.8, 137.0, 134.9, 134.4, 129.1, 128.6, 126.6, 126.2,    123.3, 122.8, 120.8, 119.7, 107.1, 106.3 (2C), 94.8 (2C), 78.3,    77.4, 69.2, 56.2 (2C), 47.0, 39.6, 38.6, 37.9, 28.5, 27.6, 26.3,    23.4, 22.9, 20.1, 16.3, 14.5, 14.3, 13.9; HRMS (EI) calcd for    C₃₉H₅₄O₈ [M⁺], 650.3819; found 650.3812. This compound is also a    compound of the invention.

Example 87-[2-(3-Hydroxy-phenyl)-vinyl]-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol(61)

CSA (17 mg, 0.073 mmol) was added to a stirred solution of stilbene 55(16 mg, 0.036 mmol) in methanol (5 mL) and the reaction mixture wasallowed to stir for 15 h at rt. The reaction mixture was concentrated invacuo and the residue was dissolved in EtOAc and water. The mixture wasextracted with ether, the organic layer was washed with brine, dried(MgSO₄), and concentrated in vacuo. Purification of the residue by flashcolumn chromatography (60% EtOAc in hexanes) afforded compound 61 (9 mg,63%) as a clear oil: ¹H NMR δ 7.26-7.19 (m, 1H), 7.06-6.85 (m, 6H),6.73-6.70 (m, 1H), 5.05 (s, 1H, exchangeable with D₂O), 3.83 (s, 3H),3.46-3.43 (m, 1H), 2.75-2.66 (m, 2H), 2.18-1.61 (m, 5H), 1.49 (br. s,1H, exchangeable with D₂O), 1.26 (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H);¹³C NMR δ 156.1, 149.2, 142.9, 139.6, 130.0, 129.4, 129.0, 126.1, 122.9,120.9, 119.3, 114.4, 112.9, 107.2, 78.3, 77.4, 56.2, 46.9, 38.6, 37.8,28.5, 27.6, 23.4, 20.1, 14.5; HRMS (EI) calcd for C₂₅H₃₀O₄ (M+H⁺),395.2222; found 395.2237.

The intermediate stilbene 55 was prepared as follows.

-   a. (3-Methoxymethoxy-benzyl)-phosphonic acid diethyl ester (38)    Methanesulfonyl chloride (1.0 mL, 12.9 mmol) was added dropwise to a    solution of alcohol 36 (500 mg, 2.97 mmol) and Et₃N (0.5 mL 3.6    mmol) in CH₂Cl₂ (10 mL) and the solution was stirred for 2 h at    0° C. The reaction mixture was allowed to warm to rt over 5 h,    quenched by addition of H₂O, and extracted with EtOAc. The combined    organic layers were washed with NH₄Cl (sat), brine, dried (MgSO₄),    and concentrated in vacuo. The resulting yellow residue was treated    with NaI (1 g, 3.6 mmol) in acetone (15 mL) for 24 h at rt. This    reaction mixture was concentrated in vacuo to afford a red solid,    which was dissolved in EtOAc. After the resulting yellow solution    was washed once with NaHCO₃ and then with Na₂S₂O₃ until the color    faded, it was extracted with ether and the combined organic layers    were dried (MgSO₄) and concentrated in vacuo. The resulting yellow    oil was added to triethyl phosphite (4 mL) and the solution was    heated at 100° C. for 20 h. After the solution was allowed to cool    to rt, it was poured into ether (10 mL). The mixture was extracted    with ether, dried (MgSO₄), and concentrated in vacuo. The initial    yellow oil was purified by flash chromatography (50% EtOAc in    hexanes) to afford phosphonate 38 (709 mg, 83%) as a light yellow    oil: ¹H NMR δ 7.20 (tr, J=7.9 Hz, 1H), 7.08-6.89 (m, 3H), 5.17 (s,    2H), 4.15-3.97 (m, 4H), 3.44 (s, 3H), 3.11 (d, J_(PH)=21.6 Hz, 2H),    1.27-1.22 (m, 6H); ¹³C NMR δ 157.1 (d, J_(CP)=3.2 Hz), 132.9 (d,    J_(CP)=8.9 Hz), 129.2 (d, J_(CP)=3.1 Hz), 123.1 (d, J_(CP)=6.5 Hz),    117.5 (d, J_(CP)=6.5 Hz), 114.5 (d, J_(CP)=3.5 Hz), 94.1, 61.8 (d,    J_(CP)=6.7 Hz, 2C), 55.6, 33.4 (d, J_(CP)=137.2 Hz), 16.1 (d,    J_(CP)=6.0 Hz, 2C); ³¹P NMR δ +25.8. Anal. Calcd for C₁₃H₂₁O₅P: C,    54.16; H, 7.34. Found: C, 53.98; H, 7.35.-   b.    5-Methoxy-7-[2-(3-methoxymethoxy-phenyl)-vinyl]-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol    (55). To a stirred suspension of NaH (27 mg, 0.68 mmol) and 15C5 (5    μL, 3 mol %) in THF was added phosphonate 38 (50 mg, 0.173 mmol) and    aldehyde 28 (20 mg, 0.066 mmol) at 0° C. and the reaction mixture    was allowed to warn to rt over 10 h. The reaction was quenched by    addition of water and extracted with EtOAc. The combined organic    layers were washed with brine, dried (MgSO₄), and concentrated in    vacuo. Final purification of the residue by flash column    chromatography (50% EtOAc in hexanes) afforded compound 55 (18 mg,    62%) as a clear oil: ¹H NMR δ 7.29-6.87 (m, 8H), 5.21 (s, 2H), 3.90    (s, 3H), 3.51 (s, 3H), 3.46-3.39 (m, 1H), 2.74-2.72 (m, 2H),    2.16-1.59 (m, 5H), 1.26 (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H) ¹³C NMR    δ 157.8, 149.2, 142.9, 139.5, 129.8, 129.3, 129.0, 126.3, 122.9,    120.9, 120.3, 115.3, 113.9, 107.2, 94.7, 78.2, 77.3, 56.3, 46.9,    38.6, 37.9, 29.9, 28.5, 27.6, 23.4, 20.1, 14.5; HRMS (ES+) calcd for    C₂₇H₃₄O₅ (M+H)⁺, 439.2484; found 439.2475. This compound is also a    compound of the invention.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A pharmaceutical composition comprising a compound of formula (XX):

wherein: R₇ and R₈ are each independently H or (C₁-C₆)alkyl; R₉ is H,(C₁-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₂-C₁₅)alkoxy, (C₁-₁₅) alkanoyl,(C₁-C₁₅)alkoxycarbonyl, (C₂-C₁₅)alkanoyloxy, aryl or heteroaryl, whicharyl or heteroaryl is optionally substituted with one or more halo,hydroxy, cyano, CF₃, OCF₃, NR^(a)R^(b), (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl,(C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, (C₁-C₁₅)alkoxy(C₁-C₁₅)alkoxy,—P(═O)(OH)₂, and(C₂-C₁₅)alkanoyloxy; R₁₀ is H or (C₁-C₆) alkyl; and R^(a) and R^(b) areeach independently H or (C₁-C₆)alkyl wherein any (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅) alkanoyl,(C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy of R₇, R₈ and R₉ isoptionally substituted with one or more halo, hydroxy, cyano, or oxo(═O) or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier.
 2. A method for treating cancercomprising administering a therapeutically effective amount of acompound of formula (XX):

wherein: R₇ and R₈ are each independently H or (C₁-C₆)alkyl; R₉ is H,(C₁-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-₁₅) alkanoyl,(C₁-C₁₅)alkoxycarbonyl, (C₂-C₁₅)alkanoyloxy, aryl or heteroaryl, whicharyl or heteroaryl is optionally substituted with one or more halo,hydroxy, cyano, CF₃, OCF₃, NR^(a)R^(b), (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl,(C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, (C₁-C₁₅)alkoxy(C₁-C₁₅)alkoxy,—P(═O)(OH)₂, and(C₂-C₁₅)alkanoyloxy; R₁₀ is H or (C₁-C₆) alkyl; and R^(a) and R^(b) areeach independently H or (C₁-C₆)alkyl wherein any (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅) alkanoyl,(C₁-C₁₅)alkoxycarbonyl, or (C₂-C₁₅)alkanoyloxy of R₇, R₈ and R₉ isoptionally substituted with one or more halo, hydroxy, cyano, or oxo(═O) or a pharmaceutically acceptable salt thereof; to a mammal.
 3. Themethod of claim 2 wherein the cancer is breast cancer or a cancer of theCNS or renal system.
 4. The composition of claim 1 wherein R₇ is H. 5.The composition of claim 1 wherein R₇ is (C₁-C₆) alkyl.
 6. Thecomposition of claim 1 wherein R₈ is H.
 7. The composition of claim 1wherein R₈ is (C₁-C₆) alkyl.
 8. The composition of claim 1 wherein R₉ isH.
 9. The composition of claim 1 wherein R₉ is (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅) alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, (C₂-C₁₅)alkanoyloxy.
 10. The composition ofclaim 1 wherein R₉ is aryl optionally substituted with one or more halo,hydroxy, cyano, CF₃, OCF₃, NR^(a)R^(b), (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl,(C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl,(C₁-C₁₅)alkoxycarbonyl, and (C₂-C₁₅)alkanoyloxy.
 11. The composition ofclaim 1 wherein R₉ is of the formula

wherein: R^(c) and R^(e) are each independently H, halo, hydroxy,(C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅) alkynyl, (C₁-C₁₅)alkoxy,methoxymethoxy, and (C₂-C₁₅)alkanoyloxy; and R^(d) is H, (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅) alkanoyl,(C₁-C₁₅)alkoxycarbonyl, and (C₂-C₁₅)alkanoyloxy; R^(g) is H, cyano,fluoro, or —P(═O)(OH)₂; and R^(h) is H, cyano, fluoro, or —P(═O)(OH)₂;wherein any (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅) alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or(C₂-C₁₅)alkanoyloxy of R^(c), R^(e), and R^(d) is optionally substitutedwith one or more halo, hydroxy, cyano, or oxo (═O).
 12. The compositionof claim 1 wherein R₉ is isoxazolyl, imidazolyl, pyridyl, indolyl, orbenzo[b]furanyl.
 13. The method of claim 2 wherein R₇ is H.
 14. Themethod of claim 2 wherein R₇ is (C₁-C₆) alkyl.
 15. The method of claim 2wherein R₈ is H.
 16. The method of claim 2 wherein R₈ is (C₁-C₆) alkyl.17. The method of claim 2 wherein R₉ is H.
 18. The method of claim 2wherein R₉ is (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅) alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl,(C₂-C₁₅)alkanoyloxy.
 19. The method of claim 2 wherein R₉ is aryloptionally substituted with one or more halo, hydroxy, cyano, CF₃, OCF₃,NR^(a)R^(b), (C₁C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅)alkanoyl, (C₁-C₁₅)alkoxycarbonyl, and(C₂-C₁₅)alkanoyloxy.
 20. The method of claim 2 wherein R₉ is of theformula

wherein: R^(c) and R^(e) are each independently H, halo, hydroxy,(C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅) alkynyl, (C₁-C₁₅)alkoxy,methoxymethoxy, and (C₂-C₁₅)alkanoyloxy; and R^(d) is H, (C₁-C₁₅)alkyl,(C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl, (C₁-C₁₅)alkoxy, (C₁-C₁₅) alkanoyl,(C₁-C₁₅)alkoxycarbonyl, and (C₂-C₁₅)alkanoyloxy; R^(g) is H, cyano,fluoro, or —P(═O)(OH)₂; and R^(h) is H, cyano, fluoro, or —P(═O)(OH)₂;wherein any (C₁-C₁₅)alkyl, (C₂-C₁₅)alkenyl, (C₂-C₁₅)alkynyl,(C₁-C₁₅)alkoxy, (C₁-C₁₅) alkanoyl, (C₁-C₁₅)alkoxycarbonyl, or(C₂-C₁₅)alkanoyloxy of R^(c) , R^(e), and R^(d) is optionallysubstituted with one or more halo, hydroxy, cyano, or oxo (═O).
 21. Themethod of claim 2 wherein R₉ is isoxazolyl, imidazolyl, pyridyl,indolyl, or benzo [b]furanyl.